Preclinical Characterization and Phase 1 Study of the Anti-HER2-TLR7 Immune Stimulator Antibody Conjugate NJH395 in Patients with HER2-positive Malignancies

Immune stimulator antibody conjugates (ISACs) combining tumor-targeting monoclonal antibodies with potent immunostimulatory agents allow targeted delivery of immune activators in tumors. NJH395 is a novel, first-in-class ISAC comprising a Toll‐like receptor 7 (TLR7) agonist conjugated to an anti-HER2 antibody via a non-cleavable linker-payload. Preclinical characterization showed ISAC-mediated activation of myeloid cells in the presence of antigen-expressing cancer cells, with antigen targeting and TLR7 agonism contributing to antitumor activity. Safety, efficacy, immunogenicity, pharmacokinetics, and pharmacodynamics were investigated in a phase 1, multicenter, open-label study in patients with HER2-positive malignancies (NCT03696771). Data from 18 patients enrolled in single ascending dose escalation demonstrated delivery of the TLR7 agonist payload in HER2-positive tumor cells and induction of type I IFN response, which interrelated with preferential immune modulation in the tumor microenvironment. Cytokine release syndrome was a common but manageable drug-related adverse event. Antidrug antibody formation and neuroinflammation at high doses represented significant clinical challenges